Our team pioneered the concepts of oral signal transduction therapy and disease stabilization endpoints and the concept of serial tumor tissue biopsies for translational endpoint analysis. We have expanded our approach to signal transduction therapy combinations and we have added microproteomic techniques for illustration of drug mechanism in serially obtained tumor samples. Our driving hypothesis is that combinations focusing on signaling steps in series or in parallel and in multiple cell lineages within the microenvironment will yield improved outcomes. Aim 1) Advance our focus on molecular signaling inhibitors on the microenvironment in ovarian cancer. The combination of sorafenib and bevacizumab was a successful phase I and proof-of-mechanism trial. The ovarian cancer phase II trial has shown activity in bevacizumab-naive women, though less activity in our limited cohort of women with prior exposure to bevacizumab, a critical finding given the toxicity and cost of bevacizumab. Serial biopsies, imaging, and blood samples have been collected and will be examined in 4Q'13 into '14. The signature identified in the phase 1 study will be examined for validation in the phase 2. The phase 2 study is ovarian cancer specific, whereas the phase 1 was all solid tumors; success of the validation will add strength to the concept that there may be cross-cancer signaling targets that behave similarly. 2) Cross-mining our translational data. We reported that high progranulin concentrations in early post-remission patient plasma prognosticated early OvCa recurrence (see also CCR/WRNMMC project). Two validation studies in serum have completed suggesting that plasma may be a more robust resource for PGRN measurements. This is scientifically sound as neutrophil elastase, activated during serum clotting cleaves PRGN into component granulins. Our Gynecologic Oncology Group study collecting serum from women undergoing surgical diagnosis of a pelvic mass has completed its accrual of over 2000 patients and the MOU for sample release has finally been completed (end FY'13); endpoints will be examined collaboratively with our DOD/WHIRC colleagues via the CCR/WRNMMC interaction and nonappropriated funds to Dr. Kohn. We also investigated and published our experience with the value, toxicity, and site information from our experience with serial biopsies from our clinical trials. This information is important to show the value, utility, and safety of this translational approach. 3) Initiate program in HRD womens cancers. Treatments for BRCA1/2 mutation associated womens cancers is a critical unmet need.This new preclinical and clinical program has been initiated by a senior medical oncology fellow in the laboratory, who has now taken it as her direction in her developing independence as a assistant clinical investigator. Our group is now a recognized center focusing on the treatment of women with BRCA1/2 mutation and BRCA-like womens cancers, homologous recombination deficient cancers. We have completed accrual and preliminarily presented our mutation carrier cohort of our phase I study of the PARP inhibitor olaparib in combination with carboplatin; a manuscript describing our experience and results of translational endpoints in blood and tissue is being completed for submission. We have been examining of sequence specificity of carboplatin and olaparib in vitro and in a clinical trial open to all womens cancers. The preclinical data are being readied for manuscript submission and the trial is nearing accrual completion. Laboratory studies investigated potential mechanisms underlying the cooperative interaction of these agents and was a collaboration with numerous CCR colleagues. 4. Examine other applications of HRD drug combinations. Our previous preclinical data indicated an interactive effect of PARP inhibition with angiogenesis inhibition, in a sequence-specific fashion. We have joined a randomized phase 2 study of olaparib v. olaparib andcediranib, based in part on our data, headed by the investigators at the Dana Farber Cancer Center. We incorporated a translational endpoint plan into the CTEP-approved randomized phase II trial of olaparib v. olaparib + cediranib for women with high grade serous and endometrioid OvCa, where all participating patients are to be seen in our clinic for sample acquisition and imaging pretherapy and on day 3; we will also be a treatment site on the trial. Biopsies will also be requested of mutation carriers at the time of progression of disease in order to further examine the issue of secondary HR enabling mutations. This trial is a collaborative study with leading groups in the HRD treatment field and a high impact, high priority trial.